5-esterified hydroxy-thiazolidine-4-carboxylic acid compounds

ABSTRACT

2,2-DISUBSTITUTED 6-ACYL-THIAZOLIDINE-4-CARBOXYLIC ACID COMPOUNDS CONTAINING IN 5-POSITION A HYDROXY GROUP ESTERIFIED BY A STRONG ACID ARE INTERMEDIATES WHICH ARE USEFUL IN THE SYNTHESIS OF 7-AMINO-CEPHALOSPORANIC ACID COMPOUNDS.

United States Patent 3,598,832 S-ESTERIFIED HYDROXY-THIAZOLIDINE-4-CARBOXYLIC ACID COMPOUNDS Robert Burns Woodward, 12 Oxford St.,Cambridge, Mass. 02138 No Drawing. Original application Aug. 22, 1966,Ser. No. 573,865, now Patent No. 3,481,948. Divided and this applicationDec. 16, 1968, Ser. No. 784,193 Claims priority, applicationSwitzerland, Sept. 10, 1965, 12,623/65; Dec. 9, 1965, 16,973/65,16,974/65; Feb. 3, 1966, 1,530/66 Int. Cl. C07d 91/14 US. Cl. 260-306.77 Claims ABSTRACT OF THE DISCLOSURE 2,2-disubstituted3-acyl-thiazolidine-4-carboxylic acid compounds containing in 5-positiona hydroxy group es terified by a strong acid are intermediates which areuseful in the synthesis of 7-amino-cephalosporanie acid compounds.

CROSS-REFERENCES TO RELATED APPLICATIONS This application is a divisionof our application Ser.- No. 573,865, filed Aug. 22, 1966, and now US.Pat. No. 3,481,948.

The present invention relates to a methodological process for themanufacture of azido compounds and the corresponding amino derivatives,which process is used in the manufacture of valuable intermediateproducts and which, in particular, was used in the first synthesis of 7-amino-cephalosporanic acid and the derivatives thereof,

3,598,832 I Patented Aug. 10, 1971 the process being specially suitablefor this synthesis.

7-amino-cephalosporanic acid has the following Formula XVI ice Thederivatives are mainly N-acyl compounds in which the acyl radicals areespecially those of active N-acyl derivatives of 7-amino-cephalosporanicacid, for example, thienylacetyl, e.g. Z-thienylacetyl, cyanoacetyl,chloroethylcarbamyl or phenylacetyl radicals or easily eliminable acylradicals such as the radical of a semi-ester of carbonic acid, forexample, the tertiary-butyloxycarbonyl radical.

1330/ C a I and carrying out the novel synthesis, for example, accordingto the following scheme of formulae:

The compound IX is converted into the desired 7- amino-cephalosporanicacid and its derivatives as follows:

4 phosphoric acid tri-dimethylamide, as well as dimethyl sulfoxide,dimethyl acetamide or a lower alkanol, for ex- The compound of theFormula X is used as an intermediate product is prepared as follows:

NaOCH 00001120013 OH O: H

OHC

OCH COOCHZOCL} OCH COOCHgCCla CH HOH C=C IH ocfi oo X Theabove-mentioned valuable products are, surprisingly, obtained byreacting a 2,2-disubstituted 3-acyl-thiazolidine-4-carboxy1ic acidcontaining a reactive esterified hydroxyl group in 5B-position, or aderivative thereof, with a salt of hydrazoic acid and, if desired,converting in a resulting 2,2-disubstituted3-acyl-5a-azido-thiazo1idine-4-carboxylic acid or a functionalderivaitve thereof, such as in a compound of the Formula VII, the azidogroup into an amino group, and/or, if desired, converting a substituentin a resulting compound into another substituent and/or, if desired,separating a mixture of isomers obtained into the single isomers.

A reactive esterified hydroxyl group is a hydroxyl group esterified withan inorganic acid, especially a strong mineral acid, for example, ahydrohalic acid, such as hydrochloric, hydrobromic or hydriodic acid, orsulfuric acid, or with a strong organic acid, for example, a strongorganic carboxylic acid, such as 4-nitrobenzoic acid, or a strongorganic sulfonic acid, such as methanesulfonic acid, p-toluenesulfonicacid, p-bromobenzenesulfonic acid or por m-nitrobenzenesulfonic acid.

The reaction between the starting material and the salts of hydrazoicacid, for example, a metal azide, such as an alkali metal azide, forexample, sodium azide or lithium azide, is advantageously carried out inthe presence of a suitable diluent, especially a polar, anhydrous orwatercontaining solvent, for example, dimethyl formamide or diethylformamide, N-methylpyrrolidone, acetonitrile or ample, methanol,ethanol, isopropanol or tertiary-butanol. Other salts of hydrazoic acidare, for example, ammonium azides, particularly organic ammonium azides,such as a tetra-aliphatic ammonium azide, for example, atetraalkylammonium azide, such as tetraethyl ammonium azide,cetyl-trimethylammonium azide or cetyl-triethylammonium azide, or atrialkyl-phenyl-lower alkyl-ammonium azide, such as benzyl-trimethylorbenzyl-triethylammonium azide; these azide compounds are advantageouslyused in the presence of solvents, such as those mentioned above, forexample, methylene chloride, acetonitril, benzene, dioxane,tetrahydrofuran, dimethyl sulfoxide, dimethyl formarnide, phosphoricacid tri-dimethylamide or mixtures thereof. If necessary, the reactionis performed with cooling or heating and/or in an inert gas atmosphere.

Conversion of the azido group into the amino group can be effected byreduction, for example, with the aid of catalytically activatedhydrogen, e.g. in the presence of a catalyst containing a metalbelonging to Group VIII of the Periodic Table, for example, palladium,under atmospheric pressure or superatmospheric pressure, or with achemical reducing agent, such as nascent hydrogen, generated, forexample, by reacting metals, metal alloys or amalgams with substancesyielding hydrogen, such as zinc, zinc alloys, for example, zinc-copper,or zinc amalgam in i the presence of acids, for example, organiccarboxylic acids, such as acetic acid, or alcohols, such as methanol,alkali metal amalgams, such as sodium or potassium amalgam, or aluminumamalgam in the presence of moist or hydrogen-yielding substances, forexample, moist ether or lower alkanols, such as methanol. Furthersuitable reagents are, for example, metal hydrides, such as alkali metalaluminum hydrides, for example, lithium aluminum hydride, alkali metaltrialkoxy-aluminum hydrides, for example,lithium-tri-tertiary-butyloxy-aluminum hydride, or organo-tin hydrides,for example, diisobutyl-tin hydride. Other agents are reducing metalsalts, e.g. chromium-(II)-compounds, for example, chromium-(II) acetateor chromium-(II) chloride, and particularly metal stannites, forexample, alkali metal, such as sodium, stannites (Na SnO as Well asmetal arsenites or thioarsenites, for example, alkali metal arsenites orthioarsenites, such as sodium arsenite (Na AsO or sodium thioarsenite(Na ASS these reagents being preferably used while cooling and inaqueous media containing, for example, water-miscible Organic solvents,such as methanol or ethanol, or sulfides with reducing properties, suchas alkali metal sulfides, for example, sodium sulfide, or ammoniumsulfides, such as those soluble in organic solvents, for example,ammonium sulfide or tetraethylammonium sulfide.

The azido group in the starting material can also be converted into anamino group by first converting it into a phosphine-imino group, forexample, by treatment with a suitable phosphine, such as a trialkylphosphine, for example, tri-n-butylphosphine, as Well as a triarylphosphine, for example, triphenyl phosphine, and then hydrolysing, forexample, by treatment with water.

The above reaction is carried out in the presence or absence ofdiluents, especially those, if desirable, that are inert towards thereactants and/or are capable of dissolving the said reactants, and/orsubstances having a catalytic action, with cooling, at room temperatureor while heating, if necessary, in a closed vessel undersuperatmospheric pressure and/ or in the atmosphere of an inert gas.

Substituents in the compounds obtained can be converted in known mannerinto other substituents. Acid derivatives that are obtained, forexample, esters, can be converted into the free acids without removal ofthe acyl group in 3-position, especially an easily eliminable acylgroup, for example, a tertiary-butyloxycarbonyl group. Thus, acarbo-diphenylmethoxy group may be converted into a free carboxyl groupunder acidic conditions, for example, in the presence of catalyticamount of an acid, such as trifiuoroacetic acid. Furthermore, it hasalso been observed, that a carboxy group esterified with a 2,2,2-trihalogeno-ethanol, especially 2,2,2-trichloroethanol, can then beconverted into a free carboxyl group by means of reducing agents.Suitable reducing agents are chemical reducing agents, for example,nascent hydrogen, obtained, for example, by reacting metal, metal alloysor amalgams with hydrogen-yielding substances, such as, zinc, zincalloys, for example, zinc copper, or zinc amalgam in the presence ofacids, for example, organic carboxylic acids, such as acetic acid, oralcohols, such as lower alkanols, alkali metal amalgams, for example,sodium or potassium amalgam, or aluminum amalgam, in the presence ofmoist ether or lower alkanols; furthermore, alkali metals, for example,lithium, sodium or potassium or alkaline earth metals, for example,calcium, in liquid ammonia, if necessary, with the addition of alcohols,for example, a lower alkanol. A carboxy group esterified with a2,2,2-trihalogenoethanol, such as 2,2,2-trichloroethanol may also beliberated by treatment with strongly-reducing metal salts, such aschromium-II-compounds, for example, chromium-II-acetate orchromium-II-chloride, preferably in the presence of aqueous mediacontaining water-miscible solvents, such as lower alkanols, lower alkanecarboxylic acids or ethers, for example, methanol, ethanol, acetic acid,tetrahydrofuran, dioxane ethyleneglycol dimethylether ordiethyleneglycol dimethylether. In this process the reductive splittingof a 2,2,2-trihalogenated ethyl ester can take place at the same time asthe reductive conversion of the azido group into the desired aminogroup.

Free carboxyl groups in resulting compounds can be converted by methodsin themselves known into their functional derivatives, for example,their esters, amides, hydrazides or azides. Thus, they can beesterified, for example, by treatment with a diazo compound, forexample, a diazo-low-alkane, for example, diazomethane or diazoethane,or with a phenyl-diazoalkane, such as phenyldiazomethane ordiphenyldiazomethane, or by reaction with a hydroxyl compound suitablefor esterification, for example, an alcohol, a phenol compound, or anN-hydroxynitrogen compound, such as a hydroxamic acid, in the presenceof an esterification agent, for example, a carbodiimide, such asdicyclohexylcarbodiimide, or carbonyldiimidazole, or by any other knownand suitable esterification process, for example, reaction with areactive ester of the hydroxy compound, especially an alcohol, and astrong inorganic acid or a strong organic sulfonic acid, if desired, inthe presence of a salt-forming base.

A functionally converted carboxy group in a resulting compound can alsobe converted by methods in themselves known into another functionallymodified carboxy group, e.g. esterified group, for example, bytransesterification, such as treatment with a hydroxy compound in thepresence of a trans-esterification catalyst. Furthermore, esters andespecially activated esters, for example, esters with N-hydroxy-nitrogencompounds, or anhydrides, for example, with chloroformic acid esters,such as methyl esters thereof, can be converted into other esters, aswell as into amides or hydrazides by reaction with other hydroxycompounds, for example, alcohols, or phenol compounds, and with ammonia,with at most secondary amines or hydrazines, respectively. A nitrogenatom containing a hydrogen in a resulting amide or hydrazide compoundcan subsequently be substituted, for example, by treatment with aderivative of a carboxylic or sulfonic acid, for example, an acidhalide, and/ or with a reactive sterified alcohol or by means of othersuitable reagents; an N-unsubstituted amide can be converted into anitrile, for example, by dehydration.

If necessary, the free amino group can be temporarily protected, forexample, by suitable acylation, during these additional process steps.

Mixtures of isomers obtained can be resolved into the single isomers byknown methods, for example, by fractional crystallization ordistillation, by adsorption chromatography (column or thin-layerchromatography) or by other processes. Resulting racemates can beresolved into the free compounds or into the antipodes by forming amixture of diastereoisomeric salts with optionally active salt-formingagents, separating the mixture into the diastereoisomeric salts andconverting the separated salts.

The invention further includes any variant of the present process inwhich an intermediate product obtainable at any stage of the process isused as starting material and any remaining steps are carried out, orthe process is discontinued at any stage thereof; furthermore, thestarting materials may be used in the form of derivatives, for example,their salts, or they may be formed during the reaction.

It is advantageous to select starting materials and reaction conditionsthat produce the compounds indicated above as being specially preferred.

The compounds obtainable by the process of the invention are2,2-disubstituted 3-acyl-5a-azido-thiazolidine- 4-carboxylic acids andthe functional derivatives thereof, especiall the compounds of theformula B1 Na CHCH Ac-N S X VIIa and the 2,2-disubstituted3-acyl-5a-amino-thiazolidine-4- carboxylic acids and especially thefunctional derivatives thereof, for example, the compounds of theFormula VIIIa $1 N 2 CHCH AcN X VIII in which Ac stands for an acylgroup, especially one of the above-mentioned acyl groups, X representsthe disubstituted carbon atom of the thiazolidine ring and R representsa free or functionally modified carboxyl group.

The acyl radicals Ac are primarily those that are present inpharmacologically active N-acyl derivatives of 7-aminocephalosporanicacid, such as thienylacetyl, for example, 2-thienylacetyl,chloroethylcarbamyl or phenylacetyl radicals, or easily eliminable acylradicals, for example, the radical of a semi-ester of carbonic acid, forexample, a tertiary butyloxycarbonyl radical, or any other suitable acylradicals of organic acids.

The radical -X represents, in particular, a group of the formula inwhich R and R represent hydrocarbon radicals, especially aliphatichydrocarbon radicals, for example, lower alkyl groups, for example,ethyl, n-propyl, isopropyl or preferably methyl groups, as well asaromatic groups, especially phenyl groups, or araliphatic hydrocarbonradicals, especially phenylalkyl groups, for example, "benzyl orphenylethyl groups, as well as functionally converted, particularlyesterified carboxy groups, such as carbo-lower alkoxy, for example,carbo-methoxy or carbethoxy groups, or, together, represent a divalenthydrocarbon radical, especially a divalent aliphatic hydrocarbonradical, for example, a lower alkylene group, for example, a 1,4-butylene or 1,5-pentylene group, as well as a phthaloyl group, orrepresent an oxo group or a thiono group. The above-mentionedhydrocarbon radicals are unsubstituted or may be substituted, forexample, by lower alkyl groups, such as methyl or ethyl groups, loweralkoxy groups, such as methoxy or ethoxy groups, halogen atoms, such asfluorine, chlorine or bromine atoms, halogenated alkyl groups, forexample, trifluoromethyl groups or other suitable groups.

The group R represents a free or preferably func tionally modifiedcarboxyl group, especially an esterified carboxyl group. The latter isesterified with any kind of hydroxy compound suitable for esterifyingcarboxylic acids, especially aliphatic alcohols, for example, alkanols,especially lower alkanols, such as methanol, ethanol, npropanol ortertiary butanol, cycloaliphatic alcohols, for example, cycloalkanols,such as cyclohexanol, or araliphatic alcohols, for example, phenylalkanols, such as benzyl alcohol or diphenylmethanol, as well as phenolcompounds, whereby the above-mentioned hydroxy compounds may beunsubstituted or may be substituted by lower alkyl, lower alkoxy ortrifluoromethyl groups or especially halogen atoms and other groups;substituted hydroxy compounds particularly suitable for esterifying thecarboxylic acid are halogenated lower alkanols, for example,2,2,2-trichloroethanol.

Other functionally converted carboxyl groups R are, for example,nitrogen-containing functionally modified carboxyl groups, for example,carbamyl groups which are unsubstituted or which may be mono-substitutedor disubstituted at the nitrogen atom by aliphatic, alicyclic, aromaticor araliphatic hydrocarbon radicals or heterocyclic radicals havingaromatic characteristics, for example, lower alkyl, cycloalkyl, phenyl,phenyl-lower alkyl, phenyl-lower alkylidene or pyridyl radicals, whichmay optionally be substituted by lower alkyl groups, free, esterified oretherified hydroxyl groups, for example, lower alkoxy, aralkoxy, loweralkanoyloxy or aroyloxy groups or halogen atoms, nitro ortrifiuoromethyl groups, as Well as by free, etherified or esterifiedhydroxyl groups, for example, the above-mentioned groups of this type,by radicals containing phosphorus or by acyl radicals, for example,radicals of carboxylic acids, such as radicals of semi-esters orsemi-amides of carbonic acid, or lower alkanoyl radicals, or of sulfonicacids, such as arylsultonic acids, for example, phenylsulfonyl radicals,as well as nitrile groups, azidocarbonyl groups or hydrazinecarbonyl aswell as azocarbonyl groups that may be monosubstituted orpolysubstituted at the nitrogen atom, for example, by theabove-mentioned substituents of he carbamyl group.

The starting materials used in the above process are new and areincluded in this invention. The said starting materials are, inparticular, the compounds of the formula in which Ac, R and X have themeanings given above and Y represents a reactive esterified hydroxylgroup. The latter is one of the above-mentioned esterified hydroxylgroups, especially a hydroxyl group esterified with one of theabove-mentioned strong organic carboxylic or sulfonic acids or with ahydrohalic acid.

The compounds used as starting materials are obtainable, for example, bytreating a derivative of a 2,2-disubstituted3-acyl-5,B-hydroxy-thiazolidine-4-carboxylic acid with an acid or afunctional derivative of an acid, and, if desired, separating aresulting mixture of isomers into the single isomers.

Functional acid derivatives are primarily acid halides, such aschlorides or bromides, for example, inorganic acid halides, such asthionyl chloride or phosphorus trichloride, or organic acid halides, forexample, oxalyl chloride or phosgene; further acid derivatives are, forexample, :anhydrides, including inner anhydrides, i.e. ketenes.Esterification of the intermediate product can also be effected withfree acids, especially organic acids in the presence of esterificationreagents.

The reaction is carried out in the presence or absence of a diluent,which is preferably inert towards the reactants and/or is capable ofdissolving them, in the pressence or absence of condensing agents and/orcatalysts, if necessary, with cooling or heating, in a closed vesseland/or in an inert atmosphere. The condensing agents used are, forexample, those which are capable of neutral izing generated acid, forexample, pyridine, it being pos sible to use liquid bases as additionalsolvents. Further condensing agents which are suitable for use in thepreparation of reactive esters are, for example, carbodiimides, such asdicyclohexylcarbodimide.

The 2,2-disubstituted 3-acyl-5,B-hydroxy-thiazolidine-4- carboxylicacids and the derivatives thereof used as intermediate products areprepared by the processes described in application Ser. No. 573,890,filed Aug. 22, 1966 (now US. Pat. No. 3,483,216); and application Ser.No. 573,891, filed Aug. 22, 1966.

Starting materials may also be obtained directly from theS-unsubstituted 2,2-disubstituted 3-acyl-thiazolidine-4- carboxylic acidderivatives, such as a compound of the Formula III, for example, bytreatment with a suitable halogenating reagent, such asbromotrichloromethane in the presence of ditertiary butyl peroxalate, orgaseous chlorine.

2,2-disubstituted 3-acyl-4-thiazoline-4-carboxylic acids or thederivatives thereof may be formed during the preparation of the startingmaterials; these by-products are formed by dehydration. Dehydration canalso occur, for example, by treating a 2,2-disubstituted3-acyl-5B-hydroxythiazolidine-4-carboxylic acid or a functionalderivative thereof with a suitable absorbent, for example, silica gel.These by-products are, in particular, compounds of the formula in whichAc, R and X have the meanings given above; they are likewise new and areincluded in the present invention. These unsaturated compounds can alsobe used as intermediate products; for example, they can be convertedinto 2,2-disubstituted 3-acyl-5-hydroxyor 5-esterifiedhydroxy-thiazolidine-4-carboxylic acids or derivatives thereof, forexample, into the compounds of the Formula V or Formula VI, by thedirect or indirect addition of water or of a suitable acid, for example,a carboxylic acid or a hydrohalic acid.

In addition to dehydration, the above-mentioned 2,2- disubstituted3-acyl-4-thiazoline-4-carboxylic acids or especially the functionalderivatives thereof can also be obtained by acylating 2,2-disubstituted3-thiazoline-4-carboxylic acids or the functional derivatives thereof.Acylation is preferably carried out with a functional derivative of anorganic carboxylic acid in one or more steps; suitable functionalderivatives are acyl halides, for example, chlorides, or acylanhydrides, as well as ketenes. Acylation is carried out in the presenceor absence of a solvent, preferably in the presence of a base, forexample, triethylamine or pyridine, if necessary, with cooling orheating.

Substituents of the resulting unsaturated by-products obtained can beconverted into other substituents by known methods, as described above.

As is shown in the above reaction scheme, the compounds resulting fromthe process of the invention can be converted into 7amino-cephalosporanic acid and the derivatives thereof; conversion canbe effected, for example, by the processes described in application Ser.No. 573,815, filed Aug. 22, 1966 (now U.S. Pat. No. 3,483,215);application Ser. No. 573,886, filed Aug. 22, 1966 (now U.S. Pat. No.3,468,933) application Ser. No. 573, 866, filed Aug. 22, 1966 (nowabandoned); and application Ser. No. 573,876, filed Aug. 22, 1966 (nowU.S. Pat. No. 3,449,336).

The following examples illustrate the invention.

EXAMPLE 1 A solution of 66 g. of L-2,2-dimethyl-3-tertiarybutyloxycarbonyl 5B-hydroxy-thiazolidine-4-carboxylic acid methyl esterin 900 ml. of anhydrous dimethylformamide is treated with 141.5 ml. ofethyl-diisopropylamine, followed by 51.7 ml. of methane sulfonylchloride, the latter being added dropwise at to 18 C. while stirringvigorously; the addition is complete after 25 minutes. The reactionmixture containing the L-2,2 dimethyl-3-tertiarybutyloxycarbonyl 5Bmethylsulfonyloxy-thiazolidine-4- carboxylic acid methyl ester of theformula ooocrr,

is stirred for one hour at room temperature, and then a solution of 73.7g. of sodium azide in 181 ml. of water is added dropwise while stirringvigorously. The addition, which is made at 20 C., is completed after 45minutes, and the reaction mixture is poured into 6000 m1. of ether. Theorganic solution is extracted twice with 100 ml. of a 20% aqueous citricacid solution each time, and washed once with 500 ml. of a coldsaturated sodium hydrogen carbonate solution and 6 times with 2000 ml.of cold saturated sodium hydrogen carbonate solution and 6 times with2000 ml. of cold water each time. After drying and evaporating under awater-jet vacuum at room temperature, a brown crude product is obtainedwhich is immediately chromatographed on 40 times the amount by weight ofsilica gel containing 5% of water. The column is prepared in purebenzene; a yellow oil is eluted with a 9:1 mixture of benzene and ethylacetate, which is dissolved in pentane and filtered through a columncontaining 54 g. of a charcoal preparation; the colorless viscousmaterial obtained after evaporating the pentane crystal- 10 lizes fromthe same volume of pentane, with refrigeration, and yields theL-2,2-dimethyl-3-tertiary-butyloxycarbonyl 50cazido-thiazolidine-4-carboxylic acid methyl ester of the formula theanalytical preparation of which melts at 55 to 56 C.; [a] =525 :1 (c.:1.07 in chloroform); infra-red absorption bands (in methylene chloride)at 4.75;, 5.70;, 5.90;/., 7.35 7.45;;, 8.40 8.65;]. and 935 ultra-violetabsorption bands (in ethanol) )r m (e=3620).

The mother liquor contains a further amount of the desired product, aswell as a small amount of the corresponding 5,8-azido compound and ofthe 2,2-dimethyl-3-tertiarybutyloxycarbonyl 4-thiazoline-4-carboxylicacid methyl ester of the formula boiling at 65 C./0.001 mm. Hg; M.P. 34to 365 C.; infra-red absorption bands (in methylene chloride) at 5.88;;,6.37;r, 7.34;t, 7.45;;, 7.62,, 8.24;i, 8.65 8.85 9.32;t, 9.82;]. and11.91.].L; ultra-violet absorption bands (in ethanol) )r 270 m;;(5:5320) and 316 m (5:5960), a greater amount of unreacted startingmaterial being isolated from the chromatogram by washing out with a 1:1mixture of ethyl acetate and benzene.

EXAMPLE 2 A solution of 33 grams of L-2-,2-dimethyl-3-tertiarybutyloxycarbonyl 55 hydroxy thiazolidine 4 carboxylic acid methyl esterin 250 ml. of anhydrous dimethylformamide is treated with 48 m1. oftriethylamine, the batch is cooled to 15 C. and then 26 ml. of methanesulfonyl chloride are added dropwise in the course of 25 minutes withstirring and with the exclusion of moisture, the temperature being keptat 15 to 20 C. by cooling. After stirring for 90 minutes at roomtemperature, 36.9 g. of sodium azide in 90 ml. of water are allowed torun into the reaction mixture containing the L-2,2-dimethyl- 3-ter'tiarybutyloxycarbonyl 55 methylsulfonyloxythiazolidine-4-carboxylic acidmethyl ester, while stirring vigorously; the batch is stirred for afurther 45 minutes at 20 C. and it is then poured onto a mixture of 250ml. of a saturated sodium chloride solution and 5 grams of citric acid.The mixture is extracted three times with 250 ml. of cyclohexane eachtime, the organic extracts obtained are washed with ml. of water,combined, dried, and evaporated under a water-jet vacuum. The crudeproduct obtained after degassing is dissolved in 600 ml. of pentane,stirred for 15 minutes with 16 g. of a charcoal preparation, filtered,and the active carbon is washed twice with 300 ml. of pentane each time.The colorless product obtained is crystallized from pentane and thedesired pureL-2,2-dimethyl-3-tertiary-butyloxycarbonyl-5a-azido-thiazolidine-4-carboxylicacid methyl ester melting at 55 to 56 C. is obtained. The mother liquorcontains a further amount of the desired products as well as a smallamount of2,2-dimethyl-3-tertiary-butyloxycarbonyl-4-thiazoline-4-carboxylic acidmethyl ester.

EXAMPLE 3 L 2,2 dimethyl 3 tertiary butyloxycarbonyl-5aazidothiazolidine4 carboxylic acid methyl ester is obtained in the manner described inExample 1 by treating L-2,2-dimethyl 3 tertiary butyloxycarbonyl 5-(4nitrobenzoyloxy)-thiazolidine-4-carboxylic acid methyl ester with sodiumazide.

The starting material used above is prepared as follows: 0.536 g. of4-nitrobenzoyl chloride and 0.25 ml. of pyridine are added to a solutiong 0.291 g. of L-2,2-dimethyl- 3-tertiary butyloxycarbonyl Bhydroxy-thiazolidine-4- carboxylic acid methyl ester in 15 ml. ofmethylene chloride; the reaction mixture is boiled for 64 hours underreflux and then diluted with 200 ml. of methylene chloride. Afterextraction with 20 ml. of aqueous citric acid and two portions of 50 ml.each of an aqueous 1 N sodium hydrogen carbonate solution, the organicphase is washed with 50 ml. of water, dried over magnesium sulfate andevaporated. The semicrystalline product so obtained is crystallized fromhexane; from the liquid phase there is obtainedL-2,2-dimethyl-3-tertiary-butyloxy-carbonyl- 5B (4 nitrobenzoyloxy)thiazolidine 4 -carboxylic acid methyl ester of the formula [a] =+1090.3 (c.=2.89 in chloroform); infra-red absorption bands (in methylenechloride) at 5.72 583a, 5.92 6.27 r, 6.57 7.25 7.45 8.6 9.2 9.88 11,110.55 11.48 and 11.90 ultra-violet absorption bands (in ethanol) A max259 m (e=21500).

EXAMPLE 4 A total of 0.5 g. of pulverized sodium azide is added to 0.525g. of crude L-2,2-dimethyl 3 tertiarybutyloxycarbonyl-SB-chloro-thiazolidine-4-carboxylic acid methyl esterin 5 ml. of absolute dimethylformamide and the mixture is stirred for 30minutes; 100 ml. of water and 100 ml. of ether are then added. Theaqueous phase is washed with ether and the combined organic extracts arewashed with water, dried, and evaporated. The residue is dissolved in 10ml. of methylene chloride, treated with 1 g. of a diatomaceous earthpreparation (Florisil) and filtered. The residue is crystallized frompentane at C. and L 2,2 dimethyl 3tertiary-butyloxy-5aazide-thiazoldine-4-carboxylic acid ester melting at52 to 54 C. is obtained.

The starting material used in the above example is prepared as follows:0.4 ml. of triethylamine is added to a silution of 0.5 gram ofiL-2,2-dimethyl-3-tertiary butyloxycar-bonyl-SB-hydroxy thiazoldine 4carboxylic acid methyl ester in ml. of methylene chloride and then astream of dry phosgene is passed through the mixture for 2 minutes.During this process the temperature of the solution rises to the boiland triethylammonium chloride precipitates. After evaporation theresidue is dissolved in 50 ml. of ether, the insoluble salt is filteredoff and the filtrate is evaporated to yield the colorlessL-2,2-dimethyl- 3 tertiary butyloxycar-bonyl 513 chlorothiazolidine-4-carboxylic acid methyl ester of the formula Whose infrared absorptionspectrum (in methylene chloride) shows bands at 5.70a, 5.90 7.26 7.40835a, 8.63;, 935 10.10,:4 and 11.67;. The product is worked up withoutfurther purification.

EXAMPLE 5 The L 2,2 dimethyl 3 tertiary butyloxycarbonyl-4-cyano-5a-azido-thiazolidine of the formula is obtained by treatingL-2,2-dimethyl 3 tertiarybutyloxycarbonyl 4 cyano 5B chloro-thiazolidinewith sodium azide by the process described in Example 1.

The starting material used in the above procedure is obtained asfollows: 0.2 ml. of triethylamine is added to a solution of 0.07 g. ofL-2,2-dimethyl 3 tertiarybutyloxycarbonyl 5,8 hydroxy-thiazolidine 4carboxylic acid amide in 5 ml. of methylene chloride, a stream ofphosgene is passed through the mixture for 2 minutes and the mixture isthen evaporated to dryness. The residue is extracted with 20 ml. of hotether, the ether solution is filtered and the residue is purified bychromatography on silica gel. The L-2,2-dimethyl 3tertiary-butyloxycarbonyl 4 cyano 5p chloro-thiazolidine of the formulais eluted with a 9:1 mixture of benzene and ethyl acetate; the productsublimes at C./0.0005 mm. Hg and its infrared spectrum (in methylenechloride) shows bands at 453a, 5.90% 7.26 15 7.36/L, 7.50,.t, 8.70;.0,938p, 11.78

and 11.9044.

EXAMPLE 6 A solution of 0.358 g. of L-2,2-dimethyl 3tertiarybutyloxycarbonyl 5,8 hydroxy-thiazolidine 4 carboxylic acidmethyl ester in 20 ml. of methylene chloride is treated with 1.5 ml. offreshly distilled di-isopropylethylamine (large excess) and 0.1 ml. ofmethane sulfonyl chloride and the reaction mixture is allowed to standin a closed vessel. After 72 hours, the main product is still startingmaterial; 0.1 ml. of additional methane sulfonyl chloride is added andthe mixture is boiled under reflux for 23 hours. The residue obtained byevaporation under mild conditions is dissolved in 250 ml. of methylenechloride, extracted twice with ice-cold citric acid of 10% strength andwashed once with water. After drying over anhydrous magnesium sulfateand evaporation, a brown, viscous oil is obtained which ischromatographed on 23 grams of silica gel containing 5% of water,2,2-dimethyl 3 tertiarybutyloxycarbonyl-4- thiazoline 4 carboxylic acidmethyl ester is obtained in the form of a viscous oil with a 98:2mixture of benzene and ethyl acetate.

The 2,2 dimethyl 3 tertiary butyloxycarbonyl- 4-thiazoline 4 carboxylicacid methyl ester is also obtained as the main product in theesterification of L-2,2-dimethyl 3 tertiary-butyloxycarbonyl 5,6hydroxy-thiazolidine 4 carboxylic acid methyl ester with methanesulfonyl chloride in the presence of a lzl-mixture of pyridine andmethylene chloride or a 1:4 mixture of collidine and methylene chlorideas solvent, the reaction mixture being worked up in the absence ofwater.

EXAMPLE 7 A mixture of 10.4 grams of 2,2-dimethyl 3 thiazoline-4-carboxylic acid methyl ester (M.P. 70-7l C.) and 17 ml. of aceticanhydride in 12.5 ml. of triethylamine and 175 ml. of toluene is boiledunder reflux for 40 hours at a bath temperature of 120 C. The brownreaction mixture is evaporated and the last traces of the reagents areremoved by diluting twice with 50 ml. of xylene each time and then with50 ml. of toluene and evaporating the solvent each time. The residue isdistilled in a high vaccum and chromatographed on silica gel; thedesired 2,2-dimethyl 3 acetyl-4-thiazoline- 4-carboxylic acid methylester of the formula,

('30 CH C=CH is eluted with a 4:1 mixture of benzene and ethyl acetateand again distilled; B.P. 8090 C./0.01 mm. Hg; M.P. 31.534 C.; infraredabsorption bands (in methylene chloride) at 5.83M, 6.00 4, 6.40/.L,7.35,u, 8.20% 9.80 1. and 11.8 2; ultra-violet absorption bands (inethanol) x 222 mg (6:6100), 275 m, (e=4200) and 321 mu (e=7850).

The starting material used in the above example is obtained as follows:27 g. of di-isopropylethylamine are added to a solution of 26.34 g. ofthe ammonium salt of 2,2-dimethyl 3 thiazoline 4 carboxylic acid in 800ml. of methanol, the reaction mixture is stirred for 15 minutes and thenevaporated under reduced pressure. The residue is dissolved in 60 ml. oftoluene, the solution is evaporated and the residue is dissolved in 600ml. of ethyl acetate, and then 19.1 grams of dimethylsulfate are added.After stirring for 21 hours, the reaction mixture is cooled in an icebath, 150 ml. of ice-cold saturated solution of sodium hydrogencarbonate in water are added, the mixture is stirred for 15 minutes, 600ml. of benzene and a small amount of water are added, and the mixture isshaken for 2 minutes, the resulting emulsion formed being clarified bythe addition of 60 ml. of a saturated aqueous sodium chloride solution.The organic phase is washed twice with 60 ml. of a saturated sodiumchloride solution; the combined aqueous solutions are extracted with 300ml. of ethyl acetate and the combined organic solutions are washed threetimes with 90 ml. of a aqueous citric acid solution each time, and oncewith 90 ml. of water and then evaporated. The reddish brown residuecrystallizes spontaneously and is extracted three times with 150 to 200ml. of boiling pentane each time, while stirring; the orange-coloredextracts are allowed to stand overnight, filtered through a layer ofmagnesium sulfate, the filtrate is concentrated to a volume of 250 ml.and allowed to stand for 12 hours at 4 C. This process yields the2,2-dimethyl 3 thiazoline-4- carboxylic acid methyl ester which melts at70.5 to 71.5 C. after recrystallization from pentane; infra-redabsorption (in methylene chloride): 5.80 7.55 815 9.28;; and 11.8 endabsorption in ultraviolet absorption spectrum (in ethanol).

EXAMPLE 8 A mixture comprising 2.906 g. of 2,2-dimethyl-3-thiazoline 4carboxylic acid 2,2,2 trichloroethyl ester, 3.06 g. of acetic anhydrideand 152 ml. of triethylamine in 50 ml. of absolute toluene is boiledunder reflux for 18 hours with the exclusion of moisture. The solventsare evaporated under a pressure of 12 mm. Hg; the reaction mixture isthen evaporated twice with 50 ml. of xylene each time under reducedpressure, the second time at 0.1 mm. Hg, and the dark residue isdissolved in methylene chloride; the solution is diluted with hexane andthe methylene chloride is again evaporated. After filtration, acrystalline material forms which is discarded; the hexane solution isevaporated and the residue is chromatographed on 145 g. of silica gelcontaining 5% of water. After washing with 100 ml. of benzene and 98:2to 92:8 mixtures of benzene and ethyl acetate, the pure 2,2-dimethyl 3acetyl 4 thiazoline 4 carboxylic acid 2,2,2-trichloroethyl ester of theformula C O O CHZC C13 C=CH is eluted with 500 ml. of :10 to 82:18mixtures of benzene and ethyl acetate; the product is crystallized frompentane at 18 C. and melts at 54.5 to 55 C. after being recrystallizedseveral times from pentane; infra-red absorption bands (in methylenechloride) at 5.80 2, 60011., 6.43,LL, 7.35/L, 7.64 1, 8-40/.L, 8.85%9.65M, 10.42,u., 11.70 1. and 1230 ultraviolet absorption spectrum (inethanol): A 228 m,u. (e=6350), 275 mp. (e=3600) and 328 m (e=8200).

The starting material is prepared as follows: 6.95 ml. of triethylamineare added to a mixture of 7.048 g. of the ammonium salt of 2,2 dimethyl3 thiazoline 4- carboxylic acid in 200 ml. of methanol, the mixture isstirred for 30 minutes and the solution is evaporated under reducedpressure. The residue is treated with 150 ml. of absolute toluene andthe mixture is evaporated; the residue is dissolved in 150 ml. ofabsolute toluene and the mixture is evaporated; the residue is dissolvedin 150 ml. of absolute tetrahydrofuran, 7 grams of N,N' carbonyldiimidazole are added and the mixture is allowed to stand for 17 hours(solution A).

0.162 gram of a 50% sodium hydride suspension in mineral oil is added to1.4 gram of imidazole in 60 ml. of absolute tetrahydrofuran, followed by7 ml. of 2,2,2- trichloroethanol. Solution A is added in the course of20 minutes While stirring and, after 1 /2 hours, the clear solution isevaporated under reduced pressure; the residue is dissolved in 60 ml. ofbenzene, evaporated and then dissolved in ml. of ether and 100 ml. ofwater. After stirring for one hour, the aqueous phase is extracted twicewith 100 ml. of benzene each time and once with 100 ml. of 1:1-mixtureof benzene and cyclohexane. The combined organic solutions are driedover magnesium sulfate, evaporated under reduced pressure, and theresidue is evaporated to dryness under reduced pressure with 75 ml. ofxylene each time. After extraction with a mixture of methylene chlorideand hexane, the methylene chloride is distilled out, the hexane solutionis isolated and evaporated, the residue is extracted with pentane andrecrystallized from pentane. This process yields 2,2- dimethyl 3thiazoline 4 carboxylic acid 2,2,2-trichloroethylether which, afterrecrystallization from pentane, melts at 83.5 to 84.5 C.; infra-redabsorption bandsv (in methylene chloride) at 5.67;,- 5.76;r, 6.067.34,u., 7.65 825p, 8.36,:r, 8.76 9.15,u., 9.50,u, 11.83;.t and 12251.4.

EXAMPLE 9 A solution of 0.435 g. of L 2,2 dimethyl 3 tertiarybutyloxycarbonyl 5;? hydroxy thiazolidine 4 carboxylic acid 2,2,2trichyoroethyl ester in 9 ml. of anhydrous dimethylformamide is treatedwith 0.7 g. of N,N- diisopropyl-N-ethylamine and then 0.35 g. ofmethanesulfonyl chloride in 2 ml. of dimethylformamide. After stirringfor 50 minutes at room temperature, about 0.5 g. of sodium azide isadded to the mixture, which contains the L 2,2 dimethyl 3 tertiarybuty1oxycarbonyl 15 5t? methylsulfonyloxy thiazolidine 4 carboxylic acid2,2,2-trichloroethylester of the formula The mixture is stirred for 2%hours, then poured onto aqueous citric acid of 20% strength andextracted with ether; the organic solution is evaporated and 0.08 g. ofthe crude product obtained is chromatographed on 20 grams of adiatomaceous earth preparation. Elution with benzene yields the pure L2,2 dimethyl 3 tertiary butyloxycarbonyl 5a azido thiazolidine 4carboxylic acid 2,2,2-trichloroethylester of the formula which melts at80 to 80.5 C. after crystallization from ether; infra-red absorptionbands (in methylene chloride) at 4.7m, 5.65 5.75 5.87 725 7.35 8.65,:4,8.83;, 9.15,:1. and 9.33;!

EXAMPLE A solution of 1.1 g. of L 2,2 dimethyl 3 tertiarybutyloxycarbonyl thiazolidine 4 carboxylic acidmethylester in ml. ofbromo-trichloromethane is treated with 2.35 g. ofditertiary-butyl-peroxalate and heated under a nitrogen atmosphere for75 minutes (i.e. until the cessation of the gas development) at a bathtemperature of 70. After evaporating under reduced pressure (firstwater-pump, then high vacuum), the viscose residue containing the L 2,2dirntheyl 3 tertiary butyloxycarbonyl 56 bromo thiazolidine 4 carboxylicacid methylester of the formula is dissolved in 8 ml. ofdimethylformamide and treated, while cooling with Water, with asaturated aqueous solution of 0.75 g. of sodium azide and allowed tostand at room temperature for one hour. After adding 30 ml. of Water,the organic portion is extracted which two portions of ml. ofcyclohexane each, the organic extracts are dried and evaporated, and theviscous residue is chromatographed on 60 g. of purified silica gel andeluted with a 39:1-mixture of benzene and ethylacetate, 40 ml. fractionsbeing taken. Upon evaporating fractions 6-9 one obtains a crude productwhich according to thin layer chromatography (silica gel; 9:1-mixture ofbenzene and ethylacetate; characteristic spot with R =0.5) and NMR andultraviolet spectra contains the L 2,2 dimethyl 3 tertiarybutyloxycarbonyl 5aazido thiazolidine 4 carboxylic acid methylester, aswell as the 2,2-dimethyl-3-tertiary butyloxycarbonyl 4- thiazolin 4carboxylic acid methyl ester, which are identical with the productsobtained according to the procedure of Example 1.

EXAMPLE 11 To a solution of 0.418 g. of L 2,2 dimethyl 3- tertiarybutyloxycarbonyl 5/3 hydroxy thiazolidine- 4 carboxylic aciddiphenylmethyl ester in 1.6 ml. dry dimethylformamide is added 0.4 ml.of N,N-diiso- 16 propyl-N-ethylamine and the mixture is treated dropwisewith a solution of 0.7E ml. methane sulfonic acid chloride in 0.2 ml. ofdimethylformamide. After stirring for 2 hours at room temperature thereis added to the reaction mixture containing the L 2,2 dimethyl 3tertiary butyloxycarbonyl 5;? methylsulfonyloxy thiazolidine- 4carboxylic acid diphenylmethylester of the formula a saturated aqueoussolution of 0.5 g. of sodium azide. The mixture is stirred at roomtemperature for 2 /2 hours and poured onto 30 ml. of water. The aqueousmixture is extracted twice with 15 ml. each of cyclohexane, the organicextracts are dried and evaporated and the viscous residue ischromatographed on 10 g. of purified silica gel with ml. of a 39:1- and160ml. of 9:1-mixture of benzene and ethyl acetate, fractions of 10 ml.being taken. Fractions 6-10 contain the L 2,2 dimethyl-3-tertiarybutyloxycarbonyl 5oz azido thiazolidine 4-carboxylic aciddiphenylmethylester of the formula which in the infrared absorptionspectrum (in methylene chloride) shows bands at 4.76 t, 5.70 4, 5.85 and5.92 whereas fractions 18-30 furnish unchanged L-2-2-dimethyl 3 tertiarybutyloxycarbonyl 5B hydroxythiazolidine-4-carboxylic aciddiphenylmethylester.

EXAMPLE 12 To a solution of 0.16 g. L-2,2-dimethyl-3-tertiarybutyloxycarbonyl-5a-azido-thiazolidine-4-carboxylic aciddiphenylmethylester in 2 ml. of benzene are added 0.15 ml. of anisoleand 0.15 ml. of trifiuoroacetic acid; the mixture is allowed to standfor 2 hours at room temperature and evaporated under reduced pressure.The residue is dissolved in 10 ml. of benzene and the solution is washedtwice with 10 ml. each of a saturated sodium hydrogen carbonatesolution. After acidifying the aqueous extract with citric acid it isextracted with methylene chloride, the organic extract is dried andevaporated, and the viscous residue is crystallized twice from hexane toyield the pure L-2,2-dimethyl-3-tertiarybutyloxycarbonyl-5aazido-thiazolidine-4-carboxylic acid of the formulaCH3 (EH-on iuac-o-o-o-N s mo om melting point 116-117"; infraredabsorption bands (in methylene chloride) at 3.25 4.75,u, 5.82 u and 5.87t.

EXAMPLE 13 A solution of 81.17 g. of benzyltriethyl ammonium azide in500 ml. of acetonitrile is added to 83.65 g. of crude L 2,2 dimethyl3-tertiary butyloxycarbonyl-5B-chloro triazolidine-4-carboxylic acidmethyl ester and the mixture is shaken until a clear brown solution isformed, then allowed to stand during 1 1 /2 hours at room temperatureand concentrated under reduced pressure. The resulting crystalline massis taken up into 1000 m1. of water and 1000 ml. of pentane; the organicphase is washed with 1000 ml. of water and the combined aqueoussolutions are back-washed with 500 ml., then with 250 ml. of pentane.The first two extracts (1500 ml.) are combined,

dried over sodium sulfate and evaporated under reduced pressure. Theoily residue is dissolved in 400 ml. of pentane, the solution is treatedwith 10 g. of a charcoal preparation, filtered through a filter aid(Celite) and the filtrate together with about 1000 ml. of washingsolution is evaporated to dryness. The oily residue crystallizes from 22g. of pentane while standing at 15 C.-for 16 hours. The product isfiltered off, washed with 'cold (l5 C.) pentane and dried, and againrecrystallized from 34 g., 17 g. and 20 g. of pentane according to theabove procedure. The resulting product is again recrystallized from 20g. of pentane, together with material isolated from the mother liquors;this time the temperature is very slowly brought to room temperature,and after the crystallization ceases, the mixture is allowed to standfor 3 hours at 7 C., for 3 hours at C., for 2 days at 15 C., and for 2hours at '-18 to 22 C. The liquid is syphoned off and the solid materialis dried under reduced pressure; one thus obtains the L-2,2-dimethyl 3tertiary butyloxycarbonyl a azidothiazolidine-4-carboxylic acid methylester, melting point 5556 C. A further amount of the product is obtainedby concentrating the mother liquors to a volume of 2 ml., cooling to 5C. and recrystallizing as above. The starting material is prepared asfollows: A solution of 0.582 g. L-2,2-dimethyl-3-tertiarybutyloxycarbonyl-Sfi-hydroxythiazolidine-4-carboxylic acid methyl esterin 2 ml. dioxane is treated With 0.405 g. of triethylamine and then with3 ml. of a l-molar solution of thionyl chloride in dioxane; thetemperature rises to 4045 C. After 2 /2 minutes, the suspension isconcentrated under reduced pressure and at room temperature, and theresidue is extracted several times with a total of 30 ml. of ether. Thesolvent is evaporated and the residue is allowed to stand at 60 C. undera water-jet-vacuum. The resulting L-2,2-dimethyl-3-tertiarybutyloxycarbonyl-Sfi-chloro-triazolidine- 4-carboxylic acid methyl esteris used without further purification; it contains only traces of thecorresponding 5u-chloro-derivative.

The starting material is also prepared as follows: A mixture of 5.82 g.of L-2,2-dimethyl-3-tertiarybutyloxycarbonyl-Sfi-hydroxy-thiazolidine4-carboxylic acid methyl esterin 20 ml. of dioxane is treated with 5.6 ml. of triethylamine and, aftercooling to C., with 30 ml. of a l-molar solution of thionyl chloride indioxane while stirring. After 3 minutes (a precipitate is being formedand sulfur dioxide evolves), 250 ml. of toluene are added, the mixtureis stirred during 1 minute, filtered and washed with 50 m1. of toluene.The combined organic solutions are cooled to 10 C., filtered andevaporated under re duced pressure at 25-30" C. The brownish oilyresidue is taken up into 150 ml. of pentane, insoluble material isfiltered off and the filtrate is evaporated under reduced pressure. Theoily residue is distilled and the slightly yellowish L 2,2 dimethyl3-tertiary butyloxycarbonyl-5,8- chlorothiazolidine-4-carboxylic acidmethyl ester is obtained at 80-85 C./ 0.001 mm. Hg; it does not containany of the 5a-chloro derivative and crystallizes, M.P. 35- 37 C.; [a]=|164'il (c.=1.05 in chloroform); infrared absorption spectrum (inmethylene chloride) with bands at 5.68;, 5.88 1, 7.38 1, 7.52 8.35 1,8.62;, 9.22 1, 935p, 10.10; and 1l.65,u.

EXAMPLE 14 A solution of 1.006 g. of L-2,2-dimethyl-3-tertiarybutyloxycarbonyl 55 chloro-thiazolidine-4-carboxylic acid methyl esterin 5 ml. of methylene chloride is treated with a solution of 1.85 g. ofbenzyl triethylammonium azide in 5 ml. of methylene chloride. Themixture is allowed to stand at room temperature during 2 hours and 10minutes, is then evaporated under reduced pressure to yield a yellowresidue and diluted with 30 ml. of pentane. After vigorously stirringfor a few minutes, the precipitate is filtered off and washed severaltimes with a total of about 50 ml. of pentane. The filtrate and thewashings are evaporated at 50 C. under reduced pressure,

ing L-2,2-dimethyl-3-tertiary butyloxycarbonyl-Swazido-'-thiazolidine-4-carboxylic acid methyl ester; a further amount of thelatter is obtained from the mother liquors.

The benzyl triethyl ammonium azide reagent is obtained as follows: Asuspension of 893 g. of an adsorbing resin in chloride form (AmberliteIRA 410) in 400 ml. of water is filled into a chromatography column of 8cm. width. After taking 1000 ml. of water, the column is washed with asolution of 140 g. of sodium azide in 1000 ml. of water, the solutionbeing passed through in the course of one hour. The excess of sodiumazide is washed out with 1750 ml. of water, and in the course of onehour a solution of 242 g. of benzyl triethyl ammonium chloride in 1000ml. of water is passed, the eluate being collected with the start of theaddition. After washing out with 1500 ml. of water, the eluate and thewashing is evaporated at 12 mm. Hg pressure in a rotatory evaporator.The resulting colorless syrup is taken up into 250 ml. of a lzl-mixtureof methylene chloride and acetonitrile and the solution is againevaporated under reduced pressure. The glass-like residue is dried at 50C./0.1 mm. Hg; the very hygroscopic benzyl triethyl ammonium azidecrystallizes and melts at about 100110 C.

EXAMPLE 15 A solution of 0.997 g. of L-2,2-dimethyl-3-tertiarybutyloxycarbonyl 5oz chloro-thiazolidine-4-carboxylic acid methyl esterin 5 ml. of methylene chloride is cooled to 18 C. and treated with asolution of 1.51 g. of benzyl triethyl ammonium azide in 10 ml. ofmethylene chloride; the mixture is allowed to stand at 20 during 6 /2hours and is then worked up as described in Example 14. The almostcolorless oil crystallizes from 0.95 g. of pentane by standing at 15 for20 hours; it is filtered OE and washed with pentane at l5. Motherliquors and washings are passed through a column with 0.3 g. of acharcoal preparation and the residue of the eluate is crystallized froma small amount of pentane. The resulting L-2,2- dimethyl-3-tertiarybutyloxycarbonyl 5a azido-thiazolidine-4-carboxylic acid methyl ester isobtained in good yields and purity.

EXAMPLE 16 A solution of 9.1 g. of tertiary butanol in 10 ml. oftetrahydrofuran is added dropwise at 0 C. in a nitrogen atmosphere to amixture of 1.4 g. of lithium aluminum hydride in 35 ml. of anhydroustetrahydrofuran while stirring. The mixture is stirred for one hour at 0C. and then a solution of 3.45 grams of L-2,2-dimethyl-3-tertiarybutyloxycarbonyl-5a-azido-thiazolidine-4-carboxylic acid methyl ester in5 ml. of tetrahydrofuran is added; the reaction mixture is kept at roomtemperature for 1%. hours, whereupon it is poured into 200 ml. ofice-water and extracted with methylene chloride. The organic phase isevaporated and the oil obtained is dissolved in ml. of pentane. Thesolution is filtered through 1 g. of a charcoal preparation, the latteris washed with 50 ml. of pentane and the combined filtrates areevaporated. The viscous residue is dissolved in 40 ml. of pentane; thesolution is allowed to stand for 3 hours at -15 C. and theL-2,2-dimethyl-3-tertiary butyloxycarbonyl 5ozaminothiazolidine-4-carboxylic acid methyl ester of the formula ooooH1:111, CH3 OH on I mo-o-o-o-N s I ll CH3 0 /C\ 19 2.93/1., 3.00 i, 5.755.90;, 620g, 7.25 1, 745g, 835g, 8.60 and 9.35 r.

EXAMPLE 17 Hydrogen is passed through a solution of 0.337 gram ofL-2,2-dimethyl-3-tertiary butyloxycarbonyl oz-aZ1dO-thiazolidine-4-carboxylic acid methyl ester in 3 ml. of ethanol for 4hours, a total of 0.6 gram of a palladium catalyst ofpalladium-on-calcium carbonate) being added in 3 portions in the courseof the first 3 hours. The reaction mixture is filtered through a filteraid (Hyfio) and the brown filtrate is evaporated. The viscous residue isextracted with citric acid and the crude product obtained isL-2,2-dimethyl-3-tertiary-butyloxycarbonyl-5aamino-thiazolidine-4-carboxylicacid methyl ester; this is combined With the product obtained in themanner described in Example 18 and the combined products are furtherprocessed in the manner described in Example 18.

EXAMPLE 1 8 To a water-cooled solution of 0.321 g. ofL-2,2-dirnethyl-3-tertiary butyloxycarbonyl 5a azido-thiazolidine-4-carboxylic acid methyl ester in 8 ml. of acetic acid of 90% strengthare added in the course of 5 minutes 2 g. of zinc powder. After afurther 10 minutes the mixture is poured onto 100 ml. of a saturatedaqueous solution of sodium hydrogen carbonate; solid sodium hydrogencarbonate is added until the pH is 8 to 9 and then ex traction isefiected with methylene chloride. The organic extract is dried andevaporated and the viscous residue is divided into a neutral portion anda basic portion by extraction with citric acid. The neutral phase of theorganic solvent yields the L-2,2-dimethyl-3-tertiary butyloxy-carbonyl5B acetyloxy-thiazolidine 4 carboxylic acid methyl ester. The product ofthe acidic aqueous extract, i.e. the basic residue is combined with theproduct obtained in the manner described in Example 17 and the combinedproducts are chromatographed on 10 g. silica gel. A 3:1 mixture ofbenzene and ethyl acetate yields the pureL-2,2-dimethyl-3-tertiarybutyloxycarbonyl-5a-amino-thiazolidine 4carboxylic acid methyl ester which melts at 62 to 65 C. afterrecrystallization from pentane.

EXAMPLE 19 After a short treatment with a 10% aqueous sodium hydroxidesolution, 2 g. of finely granulated aluminum are washed with water andthen treated with a 0.5% aqueous mercury-(II)-chloride solution. Asolution of 0.746 g. of L2,2-dimethyl-3-tertiary-butyloxycarbonyl-5a-azidothiazolidine-4-carboxylicacid methyl ester in 10 ml. of ether is added to the amalgam which hasbeen Washed with water; after 10 minutes the ether solution is decanted,dried and evaporated. The viscous residue is chromatographed on 25 g. ofsilica gel and the desired L-2,2-dimethyl 3 tertiary butyloxycarbonyl 5a amino-thiazolidine-4-carboxylic acid methyl ester is eluted with a 3:1mixture of benzene and ethyl acetate; the product melts at 64 to 66 C.after crystallization from pentane.

EXAMPLE A solution of 3.16 g. of L-2,2-dimethyl-3-tertiarybutyloxycarbonyl 5a azido thiazolidine 4 carboxylic acid methyl ester in50 ml. of anhydrous benzene is treated dropwise with 2.2 g. oftri-n-butyl-phosphine While maintaining a nitrogen atmosphere. Themixture is allowed to stand for 5 hours at room temperature; the yellowsolution, which contains the L-2,2-dimethyl-3-tertiary butyloxycarbonyl5a tri-n-butylphosphinimino thiazolidine-4-carboxylic acid methyl ester,is then poured into 50 ml. of water and the mixture is stirred for 15hours. After evaporation the residue of the benzene solution istriturated with pentane, the pentane solution is washed three times with100 ml. of water each time and evaporated. The viscous residue ischromatographed on 200 grams of silica gel and the desiredL-2,2-dimethyl-3- 20 tertiary butyloxycarbonyl 504 amino thiazolidine 4-carboxylic acid methyl ester is eluted with a 3:1 mixture of benzene andethyl acetate; it is identical with the product obtained in Examples 16,18 and 19.

L 2,2 dimethyl 3-tertiary butyloxycarbonyl 50!.-tripheny1-phosphinimino-thiazolidine 4 carboxylic acid methyl ester,which can be used in the same way, is obtained in the following manner:

A solution of 0.316 g. ofL-2,Z-dimethyl-3-tertiary-butyloxycarbonyl-5a-azido-thiazolidine 4carboxylic acid methyl ester in 15 ml. of pure methylene chloride istreatedw ith 0.2623 g. of recrystallized triphenylphosphine and themixture is boiled under reflux for 3 /2 hours. Cautious evaporationproduces a white, foam-like material which crystallizes from hexanecontaining a small amount of methylene chloride; theL-2,2-dimethyl3-tertiary-butyloxycarbonyl 5a -triphenyl phosphiniminothiazolidine- 4-carboxylic acid methyl ester of the formula so obtainedmelts at 173 to 175 C. after drying in a high vacuum; [u] =67:1(c.=1.247 in chloroform); infra-red absorption bands (in methylenechloride) at 5.79 1., 5.91/L, 6.14 t, 6.8 7.02 t, 7.29 1, 7.38,, 7.44836 8.60/L, 9.07 1, 9.35 1, 9.78 4, 10.09/L, 10.66 11. and 11.65 14ultraviolet absorption bands (in ethanol) A 220 mp. (e=25000) and 268 m(6 2420).

It can also be obtained in the following manner:

A solution of 0.427 g. of triphenylphosphine in 5 ml. of hexane is addedto a solution of 0.485 g. of pure L-2,2- dimethyl 3 tertiarybutyloxycarbonyl 5a azido thiazolidine-4-carboxylic acid methyl ester in5 ml. of hexane and the mixture is heated to C. Crystallization startsafter about 2 minutes, the vessel is closed and the mixture is allowedto cool. After 2 hours at 0 C. the supernatant solution is decanted andthe crystalline material is washed with 5 ml. of pentane and dried; theproduct so obtained melts at 180 to 181 C. and is identical with theproduct obtained by the process described above.

EXAMPLE 21 A mixture of 58.2 g. ofL-2,2-dimethyl-3-tertiary-butyloxycarbonyl 5a azido thiazolidine 4carboxylic acid methyl ester in 750 ml. of methanol, 750 ml. ofcyclohexane and 350 ml. of hexane is cooled to l-8 C. while stirring,and treated in a vessel having a vibration stirrer with aluminum amalgam(prepared by treating 10 g. of aluminum shavings with a 2 N sodiumhydroxide solution and then with mercury-(II) chloride, followed bywashing with water and then with anhydrous methanol). The mixture isthen Washed with a small amount of methanol. After 40 hours at 15 to 18C., unreacted starting material is still detectable; 5 grams of freshlyprepared aluminum amalgam are added and stirring is continued for afurther 8 hours at l8 C. After filtration and Washing with methanol, theinorganic residue is boiled for a short time with methanol and thesolution is combined with the filtrate. The combined organic solutionsare evaporated and the oily residue is extracted with pentane. Thepentane solution is evaporated to a volume of 250 to 300 ml., allowed tostand at -18 C. and is then decanted from the semi-crystalline product.The latter is Washed with a small amount of pentane and recrystallizedfrom pentane; the L-2,Z-dimethyl-3-tertiary-butyloxy-carbonyl- 5aamino-thiazolidine-4-carboxylic acid methyl ester is dissolved inpentane, filtered through anhydrous magnesium sulfate, concentrated to avolume of to 200 ml. and crystallized; after further recrystallizationfrom pentane the ester obtained melts at 64 to 65 C.

21 EXAMPLE 22 A solution of 0.141 g. ofL-2,2-dimethyl-3-tertiary-butyloxy carbonyl a azido thiazolidine 4carboxylic acid methyl ester in 15 ml. of methanol is cooled to -15 C.and then 0.3 g. of chromium-(II)-acetate is added; a further amount of0.24 g. of the reducing agent is added after 35 minutes. After stirringfor 4 hours at to -18 C., the reaction mixture is filtered, the residueis washed with methanol and 50 ml. of cyclohexane and the filtrate isevaporated under reduced pressure. The residue is extracted withcyclohexane and a mixture comprising theL-2,2-dimethyl-3tertiary-butyloxycarbonyl-Sat-aminothiazolidine-4-carboxylicacid methyl ester and the corresponding SB-amino compound is obtainedwhich can be separated by means of a thin-layer chromatogram.

EXAMPLE 23 A solution of 0.32 g. ofL-2,2-dimethyl-3-tertiary-butyloxycarbonyl 5a azido thiazolidine 4carboxylic acid methyl ester in a mixture of 0.47 g. ofdi-n-butyl-tindihydride and 1 ml. of hexane is allowed to stand for 18hours at room temperature in a nitrogen atmosphere. A total of 30 ml. ofpentane is added, the mixture is extracted three times with 20 ml. of a20% aqueous citric acid solution each time, the aqueous solutions aresaturated with solid sodium hydrogen carbonate and extracted withmethylene chloride. The residue from the organic extracts is dissolvedin pentane, filtered through 2.5 grams of a charcoal preparation(Carboraffin) and washed with 40 ml. of methylene chloride. Afterevaporation, the residue is crystallized from pentane at 20 C.; the pureL 2,2 dimethyl 3 tertiary butyloxycarbonyl 5aaminothiazolidine-4-carboxylic acid methyl ester so obtained melts at 64.5 to65.5 C.

EXAMPLE 24 A mixture of 0.3164 g. ofL-2,2-dimethyl-3tertiary-butyloxycarbonyl 50c azido thiazolidine 4carboxylic acid methyl ester in 10 ml. of methanol and 1 m1. of aceticacid is treated with 5 g. of sodium amalgam (5%), the mixture is stirredfor 2 minutes, filtered and evaporated. The residue, which stillcontains starting material, is dissolved in 10 ml. of dioxane and 0.6ml. of acetic acid; 5 g. of sodium amalgam are added and the mixture isstirred for minutes. After working up in the manner described above theresidue is dissolved in ml. of methylene chloride and extracted 5 timeswith a 20% aqueous solution of citric acid each time. The acidicsolution is worked up in the manner described in the foregoing examplesand a crude product is obtained which consists mainly ofL-2-,2-dirnethyl-3tertiary-bhtyloxycarbonyl-5a-amino-thiazolidiue 4carboxylic acid methyl ester.

EXAMPLE A solution of 0.973 g. of L-2,2-dimethyl-3-tertiarybutyloxycarbonyl-5(1-azido-thiazolidine-4-carboxylic acid methyl esterin 25 ml. of methanol and 2.40 ml. of acetic acid is cooled to 8 C.; 0.5g. of magnesium shavings is added and the reaction is started by theaddition of a few crystals of mercury-(II)-chloride. After stirring for90 minutes at 5 C. to 8 C., 0.25 g. of magnesium followed by 1.2 ml. ofacetic acid and a trace of mercury-(*ID-chloride are added. Afterstirring for a further 2 hours the reaction mixture is filtered andwashed with methanol; the organic solutions are combined and thenevaporated to dryness under reduced pressure. The residue is dissolvedin 130 ml. of water (pH about 8), extracted three times with 50 ml. ofmethylene chloride each time and the dried extracts are evaporated. Theoil obtained crystallizes from pentane (l0 C.) and theL-2,2-dimethyl-3-tertiarybutyloxycarbonyl-5aamino-thiazolidine-4-carboxylic acid methyl estermelts at 63 to 65 C. after recrystallization from the same solvent.

EXAMPLE 26 A solution of 9.96 g. ofL-2,2-dimethyl-3-tertiarybutyloxycarbonyl-5a-azido-thiazolidine-4-carboxylicacid methyl ester in 300 ml. of methanol is cooled to 9 C.; 9 g. ofaluminum amalgam are added and the mixture is stirred for 6 hours at 10to 0 C. After filtration and Washing with methanol, the combined organicsolutions are evaporated under reduced pressure; the colorless syrupyresidue is extracted with 200 ml. of warm pentane and the organicextracts are evaporated. The residue insoluble in pentane is trituratedwith 250 ml. of methanol and the separated methanol solution isevaporated under reduced pressure. The pentane-soluble andmethanol-soluble fractions are combined and crystallized from about 30ml. of pentane; after recrystallization from pentame :theL-2,2-dimethyl-3-tertiarybutyloxycarbonyl-5maminothiazolidine4-carboxylic acid methyl ester meltsat 64 to 66 C.

By prolonging the reaction time to 11 hours at -l0 C. to 15 C. the yieldof L-2,2-dimethyl-3tertiarybutyloxycarbonyl-5waminothiazolidine-4-carboxylic acid methyl ester isincreased; a further amount of the desired material is obtained from themother liquor of crystallization.

EXAMPLE 27 A mixture of 0.316 g. of L-2,2-dimethyl-3-tertiarybutyloxymrbonyl-Sa-azido-thiazolidine-4-carboxylic acid methyl ester in3 ml. of methanol and 2.5 ml. of acetic acid is treated at roomtemperature and while stirring with 0.05 g. of aluminum amalgam. Themixture is stirred for one hour, filtered, Washed, evaporated, and theresidue is extracted with pentane; the product obtained afterevaporation still contains unreaoted starting material, and 0.215 g. ofthe crude product is stirred for a further 230 minutes in 3 ml. ofmethanol and 2 ml. of acetic acid with 0.07 g. of aluminum amalgam.After the usual working up procedure, L-2,2-dimethyl-3tertiarybutyloxycarbonyl-Sa-aminO-thiazolidine-4-carboxylic acid methyl ester isobtained, M.P. 61 to 65 C. after recrystallization from pentane.

EXAMPLE 28 While stirring, 2 g. of zinc dust are added in portions andin the course of 5 minutes to a solution of 0.26 g. ofL-2,2-dimethyl-3tertiary butyloxycarbonyl 5aazidothiazolidine-4-carboxylic acid 2,2,2-trichloroethyl ester in 8 ml.of aqueous acetic acid of strength. After stirring for 2 /2 hours atroom temperature, the reaction is filtered, the residue is washed with 2ml. of glacial acetic acid and 5 ml. of methylene chloride and thefiltrate is evaporated. The residue is stirred several times withmethylene chloride, the organic solution is Washed with 10 ml. of Water,dried, and evaporated. The residue contains a mixture ofL-2,2-dimethyl-3-tertiarybutyloxycarbonyl-5a-amino-thiazolidine-4-carboxylic acid of the formula@0011 NH; 311, /CHCE HzC-C-O-C-N s I ll CH3 0 o H30 CH3 and2,2-dimethyl-3-tertiary butyloxycarbonyl-44hiazolidine-4-carboxylic acidof the formula coon CH3 O=CH nao-o-o-o-N s I has o 1130 oni The solutionof the crude product in methylene chloride is extracted 3 times with 20ml. of 20% aqueous citric acid each time. The acidic extracts areadjusted to a pH value of about with sodium carbonate and the aqueoussolution is extracted three times with 20 ml. of methylene chloride.Drying and evaporation yields the amorphous L-2,2-dimethyl-3-tertiarybutyloxycarbonyl 5a aminothiazolidine-4-carboxylic acid which, in theinfra-red absorption spectrum, shows bands (in methylene chloride) at2.84,, 2.93 5.76 5.90 7.37,. and 8.63

EXAMPLE 29 A solution of 0.121 g. ofL-2,2-dimethyl-3-tertiarybutyloxycarbonyl-Su-azido-thiazolidine-4-carboxylicacid 2,2,2-trichloroethyl ester in ml. of methanol is cooled to C. andtreated with 0.5 g. of aluminum amalgam. The reaction mixture is stirredfor 55 hours at 20 C., for 22 hours at 0 C. and for 18 hours at C. Theinsoluble material is filtered 01f and the filtrate is evaporated toyield an oily residue which according to thin layer chromatographycontains starting material and an about equal amount of the more polarL-2,2-dimethyl-3- tertiary-butyloxycarbonyl 50amino-thiazolidine-4-carboxylic acid 2,2,2-trichloroethylester of theformula the infrared absorption spectrum of the latter (in methylenechloride) shows characteristic bands at 2.85 1. and 2.92,u.

The filter residue is dissolved in aqueous tartaric acid and extractedwith methylene chloride to yield a mixture of tartaric acid and of theL-2,2-dimethyl-3-tertiarybutyl-oxycarbonyl-S-amino-thiazolidine-4-carboxylicacid, which is identical with the product obtained according to themethod described in Example 28.

The starting material is prepared as described in Example 9; instead oftheL2,2-dimethyl-3-tertiary-butyloxycarbonyl-S/S-methylsulfonyloxy-thiazolidine4 carboxylic acid 2,2,2-trichloroethyl ester one may also use as anintermediate theL-2,2-dimethyl-3-tertiary-butyloxycarbonyl-SB-chloro-thiazolidine-4-carboxylicacid 2,2,2- trichloroethyl ester, which may be prepared as follows: asolution of 0.409 g.L-2,2-dimethyl-3-tertiary-butyloxycarbonyl-Sfi-hydroxy-thiazolidine-4-carboxylicacid, 2,2,2- trichloroethyl ester in 5 ml. dioxane is treated with 0.3ml. triethylamine; the clear solution is cooled to 10 C. and 1.5 ml. ofa l-molar solution of thionyl chloride in dioxane is added. Shortlyafter completion of the addition a precipitate is formed and the colorchanges to yellow. The suspension is concentrated at room temperatureunder reduced pressure to a volume of about 2 ml. and 25 ml. of tolueneare added. After 2 minutes the suspension is filtered, the removed saltis washed with toluene and the filtrate is evaporated under reducedpressure and at room temperature to yield a yellow oily product, whichis extracted with n-hexane. After evaporating the solvent under reducedpressure and at room temperature, the resulting clear yellow oil isdissolved in n-hexane and treated with a charcoal preparation(Carborafi'in) and the desiredL-2,2-dimethyl-3-tertiary-butyloxycarbonyl 5Bchlorothiazolidine-4-carboxy1ic acid 2,2,2-trichloroethyl ester of isobtained as a colorless oil. @1 +95il to: 1.005 in chloroform); infraredabsorption spectrum {in methyl- 24 ene chloride) with bands at 5.65 5.724, 5.9a, 8.65 9.2a, 9.3514, and 9.85

EXAMPLE 30 0.74 g. of arsenic bisulfide (realgar, As S is added to asolution of 1.2 g. of sodium sulfide in 3 ml. of water, and resultingsolution is treated at 0 C. with a solution of 0.158 g. ofL-2.2-dimethyl-3-tertiarybutyloxycarbonyl-5uazido-thiazolidine-4-carboxylic acid methyl ester in3 ml. of ethanol. The reaction mixture is stirred at 0 C. for 15 minutesuntil gas ceases to evolve and then extracted with methylene chloride.The residue obtained after evaporating the organic extract shows in thethin-layer chromatogram (system: 3:1 mixture of benzene and ethylacetate) the presence of starting material; infrared bands 1 inmethylene chloride) at 4.70 and of L-2,2-dimethyl-3- tertiarybutyloxycarbonyl-Sa-amino-thiazolidine 4 carboxylic acid methyl ester;characteristic infrared bands (in methylene chloride) at 2.90 14, 2.9710.05, and 10.25 contaminated by the corresponding SB-amino ester.

EXAMPLE 31 A mixture of 0.222 g. of stannous chloride dihydrate (SnCl-2H O) in 4 ml. of a 1 N sodium hydroxide solution is stirred for 5minutes at 0 C., the resulting suspension is filtered and the insolubleportion washed with 1 ml. of water. The filtrate is cooled to 0 C. andadded in one portion to a solution, cooled to 0 C., ofL-2,2-dimethyl-3-tertiary-butyl-oxycarbonyl cazido-thiazolidine-4-carboxylic acid methyl ester in 5 ml. of absoluteethanol; the reaction vessel is cooled in an ice-bath and the reactionmixture stirred for 5 minutes until gas ceases to evolve. After theaddition of 5 ml. of water the batch is extracted once with 10 ml. andonce with 3 ml. of methylene chloride and the extracts dried over sodiumsulfate are evaporated. The colorless oily residue is crystallized from1 ml. of pentane (0 C., 16 hours) and recrystallized from the samesolvent; the resulting L-2,2- dimethyl-3-tertiary-butyloxycarbonyl 5ozamino-thiazolidine-4-carboxylic acid methyl ester melts at 6165 C.

EXAMPLE 32 A mixture of 0.63 g. of stannous chloride dihydrate isstirred for 5 minutes at 0 C. with 6.8 ml. of 1 N sodium hydroxidesolution and the mixture added in one portion to an ice-cooled solutionof 0.332 g. of L-2,2-dimethyl-3-tertiary-butyloxycarbonyl-5u-azido-thiazolidine 4 carboxylic acid methylester in 5 ml. of tetrahydrofuran. The reaction mixture is stirred at 0C. for 5 minutes and 10 ml. of water and 30 ml. of methylene chlorideare then added. The organic phase is evaporated under reduced pressure;the resulting oily residue still contains a large amount of startingmaterial and is treated as follows: 0.324 g. of the resulting product in6 ml. of tetrahydrofuran is cooled to 0 C. and treated with a sodiumstannite suspension (prepared from 0.61 g. of stannous chloridedihydrate and 6.7 ml. of 1 N sodium hydroxide solution (5 minutes, 0C.)) and stirred with a magnetic stirrer for one hour at 0 C. Thereaction mixture is worked up as described above; the colorless oilyproduct crystallizes on standing and is recrystallized from 1.6 g. ofpentane at l5 C.; the resulting L2,2-dimethyl3-tertiary-butyloxycarbonyl-Sa-amino-thiazolidine 4 carboxylic acid methylester, after further crystallization from 1 g. of pentane, melts at64-65.5 C.

EXAMPLE 3 3 .A solution of 0.166 g.L-2,2-dimethyl-3-tertiary-butyloxycarbonyl-5a-azido-thiazolidine-4-carboxylicacid 2,2,2- trichloroethyl ester in 10 ml. of dry ethanol is cooled to 0C. A slurry of sodium stannite, prepared by treating at 0 C. 0.3 g. ofstannous chloride dihydrate with 4 ml. of a 1 N sodium hydroxidesolution in water for five minutes, is added in one portion to thesolution and the mixture is stirred at 0 for 2 /2 minutes. The reactionis stopped by adding 1 ml. of a 20% aqueous citric acid 25 solution, andthe reaction mixture is diluted with ml. of water and extracted oncewith 20 ml. and once with 10 ml. of methylene chloride. The driedorganic extracts are evaporated under reduced pressure, the resultingoil is dissolved in pentane, the solution is filtered, concentrated to avolume of about 1 ml. and cooled to for 16 hours. The crystallineL-2,2-dimethyl 3tertiarybutyloxycarbonyl-Sa-amino-thiazolidine-4-carboxylic acid,2,2,2-trichloroethyl ester melts at 49-62 C.; infrared absorption bands(in methylene chloride) at 2.85-2.9n, 5.70 5.855.98,LL (broad), 6.25,u,7.40 8.65 and 9.40

1. A compound of the formula Bi oH-oH-Y in which Ac represents a readilyeliminable acyl residue of a semi-ester of carbonic acid, X stands forthe group of the formula in which each of R and R stands for loweralkyl, and R is a member selected from the group consisting of a freecarboxyl group, a carboxyl group esterified with a lower alkanol, ahalogenated-lower alkanol or a phenyllower alkanol and a nitrile group,and Y represents a hydroxyl group esterified with a strong organiccarboxylic or sulfonic acid selected from the group consisting of 4-nitrobenzoic acid, methane sulfonic acid, p-toluenesulfonic acid,p-bromobenzenesulfonic acid and por m-nitrobenzenesulfonic acid, ahydrohalic acid or sulfuric acid.

2. A compound as claimed in claim 1 and being a compound of the formulain which Ac represents readily eliminable acyl residue of a semiester ofcarbonic acid and R is a carboxyl group esterified with a memberselected from the group consisting of a lower alkanol and a halogenatedlower alkanol, and Y is a hydroxyl group reactively esterified by amember selected from the group consisting of a hydrohalic acid, sulfuricacid, 4-nitro-benzoic, methane sulfonic, p-toluene sulfonic,p-bromobenzene sulfonic, p-nitrobenzene sulfonic and m-nitrobenzenesulfonic acid.

3. A compound as claimed in claim 1 and being L-2,2- dimethyl-3-tertiarybutyloxycarbonyl-5fl-methyl-sulfonyl oxythiaZolidine-4-carboxylic acidmethyl ester.

4. A compound as claimed in claim 1 and being L-2,2- dimethyl-3-tertiarybutyloxycarbonyl-SB-(4-nitrobenzoyloxy)-thiazolidine-4-carboxylic acidmethyl ester.

5. A compound as claimed in claim 1 and being L-2,2- dimethyl-3-tertiarybutyloxycarbonyl-SB-chloro thiazolidine-4-carboxylic acid methyl ester.

6. A compound as claimed in claim 1 and being L-2,2- dimethyl-3-tertiarybutyloxycarbonyl-Sfl-methyl-sulfonyloxythiazolidine-4-carboxylic acid2,2,2-trichloroethyl ester.

7. A compound as claimed in claim 1 and being L-2,2- dimethyl-S-tertiarybutyloxycarbonyl-Sfi-bromo thiazolidine-4-carboxylic acid methyl ester.

References Cited UNITED STATES PATENTS 2,934,540 4/1960 Sheehan 260-306]3,481,948 12/ 1969 Woodward 260'-306.7

ALEX MAZEL, Primary Examiner R. J. GALLAGHER, Assistant Examiner

